U.S. patent application number 13/999356 was filed with the patent office on 2014-08-14 for methods of treatment directed to neointimal proliferation generated by endothelial shear stress patterns from drug-eluting bioresorbable vascular scaffold implantation.
This patent application is currently assigned to ABBOTT CARDIOVASCULAR SYSTEMS INC.. The applicant listed for this patent is ABBOTT CARDIOVASCULAR SYSTEMS INC.. Invention is credited to RICHARD RAPOZA.
Application Number | 20140228932 13/999356 |
Document ID | / |
Family ID | 51297990 |
Filed Date | 2014-08-14 |
United States Patent
Application |
20140228932 |
Kind Code |
A1 |
RAPOZA; RICHARD |
August 14, 2014 |
Methods of treatment directed to neointimal proliferation generated
by endothelial shear stress patterns from drug-eluting
bioresorbable vascular scaffold implantation
Abstract
Treatments of coronary heart disease including the effect of
endothelial shear stress (ESS) on neointimal formation following a
bioresorbable vascular scaffold implantation are disclosed.
Inventors: |
RAPOZA; RICHARD; (SAN
FRANCISCO, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ABBOTT CARDIOVASCULAR SYSTEMS INC. |
SANTA CLARA |
CA |
US |
|
|
Assignee: |
ABBOTT CARDIOVASCULAR SYSTEMS
INC.
SANTA CLARA
CA
|
Family ID: |
51297990 |
Appl. No.: |
13/999356 |
Filed: |
February 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61765001 |
Feb 14, 2013 |
|
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|
Current U.S.
Class: |
623/1.15 |
Current CPC
Class: |
A61F 2/82 20130101 |
Class at
Publication: |
623/1.15 |
International
Class: |
A61F 2/82 20060101
A61F002/82 |
Claims
1. A method of treating vascular disease in a patient comprising:
deploying a bioabsorbable polymer scaffold composed of a plurality
of struts at a segment of an artery of a patient, the polymer
scaffold expanding during deployment which expands the segment to a
target diameter such that struts of the scaffold are apposed on a
wall of the segment, wherein immediately upon deployment the struts
disrupt flow of blood through the segment resulting in
recirculation zones upstream and downstream of the struts that are
in gaps between struts, wherein the recirculation zones are exposed
to a low shear stress from the blood flow less than 1 Pa for at
least 60% of a surface of the struts and abluminal surfaces of the
struts are exposed to a higher shear stress of at least 2 Pa, and
wherein at least one year after deployment neointimal formation is
higher in the recirculation zones than on the abluminal surfaces of
the struts.
2. The method of claim 1, wherein a least one year after deployment
a mean of the neointimal thickness is between 100 and 115 .mu.m and
a percentage volume obstruction of the a lumen of the segment by
the scaffold is less than 10%.
3. The method of claim 1, wherein the struts are embedded in the
wall.
4. The method of claim 1, wherein the struts are protruding from
the wall.
5. The method of claim 1, wherein the struts are not in contact
with the wall.
6. The method of claim 1, wherein the thickness (T)/width (W) is
greater than 1.2.
7. The method of claim 1, wherein the thickness (T)/width (W) is
less than 0.8.
8. A method of treating vascular disease in a patient comprising:
expanding a bioabsorbable polymer in a segment of an artery of a
patient such that the scaffold is expanded against a wall of the
segment, wherein the scaffold comprises a coating including a
polymer and a drug and the drug elutes from the coating into the
artery, wherein flow of blood past the scaffold through the segment
results in regions of low shear stress and regions of high shear
stress immediately after the expanding, wherein after at least 80%
of the drug elutes from the coating the regions of low shear stress
promote neointimal proliferation resulting in a negative
correlation between shear stress immediately after the expanding
and the neointimal proliferation at least one year after the
expanding.
9. A method of treating vascular disease in a patient comprising:
deploying a bioabsorbable polymer scaffold composed of a plurality
of struts at a segment of an artery of a patient, the polymer
scaffold expanding during deployment which expands the segment to a
target diameter such that some of the struts of the scaffold are in
contact with a wall of the segment, wherein immediately after
deployment at least some of the struts are malapposed such that an
abluminal surface of the malapposed struts is not in contact with
the wall of the segment, wherein immediately upon deployment the
malapposed struts disrupt flow of blood through the segment
resulting in recirculation zones upstream and downstream of the
struts that are in gaps between the malapposed struts, wherein the
recirculation zones are exposed to a low shear stress from the
blood flow less than 1 Pa for at least 60% of a surface of the
malapposed struts and abluminal surfaces of the struts are exposed
to a higher shear stress of at least 2 Pa, and wherein at least one
year after deployment neointimal formation is higher in the
recirculation zones than on the abluminal surfaces of the struts.
Description
[0001] This application claims the benefit of U.S. Application Ser.
No. 61/765,001 filed Feb. 14, 2013 and is incorporated by reference
herein for all purposes.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to methods of treatment of coronary
and peripheral artery disease of human patients with bioresorbable
polymer scaffolds, in particular, treatments in which shear stress
of blood flow past such scaffolds effects neointimal formation.
[0004] 2. Description of the State of the Art
[0005] This invention relates generally to methods of treatment
with radially expandable endoprostheses that are adapted to be
implanted in a bodily lumen. An "endoprosthesis" corresponds to an
artificial device that is placed inside the body. A "lumen" refers
to a cavity of a tubular organ such as a blood vessel. A stent is
an example of such an endoprosthesis. Stents are generally
cylindrically shaped devices that function to hold open and
sometimes expand a section or segment of a blood vessel or other
anatomical lumen such as urinary tracts and bile ducts. Stents are
often used in the treatment of atherosclerotic stenosis in blood
vessels. "Stenosis" refers to a narrowing or constriction of a
bodily passage or orifice. In such treatments, stents reinforce
body vessels and prevent restenosis following angioplasty in the
vascular system. "Restenosis" refers to the reoccurrence of
stenosis in a blood vessel or heart valve after it has been treated
(as by balloon angioplasty, stenting, or valvuloplasty) with
apparent success.
[0006] Stents are typically composed of a scaffold or scaffolding
that includes a pattern or network of interconnecting structural
elements or struts, formed from wires, tubes, or sheets of material
rolled into a cylindrical shape. This scaffold gets its name
because it physically holds open and, if desired, expands the wall
of a passageway in a patient. Typically, stents are capable of
being compressed or crimped onto a catheter from a fabricated
diameter to a reduced diameter so that they can be delivered to and
deployed at a treatment site.
[0007] Delivery includes inserting the stent through small lumens
using a catheter and transporting it to the treatment site.
Deployment includes expanding the stent to a larger target diameter
once it is at the desired location. During deployment the stent
makes contact with the vessel wall as it expands and expands the
vessel to the larger target diameter. Mechanical intervention with
stents has reduced the rate of restenosis as compared to balloon
angioplasty.
[0008] Stents are used not only for mechanical intervention but
also as vehicles for providing biological therapy. Biological
therapy uses medicated stents to locally administer a therapeutic
substance to a blood vessel. The therapeutic substance can also
mitigate an adverse biological response to the presence of the
stent. For example, the stent can deliver an antiproliferative
agent to the vessel to prevent or mitigate neointimal proliferation
caused by the stent implantation which could result in narrowing of
the vessel at the site of the stent implantation. Additionally or
alternatively, an anti-inflammatory agent can be delivered to
reduce inflammation to the vessel wall due to the stent
implantation.
[0009] A medicated stent may be fabricated by coating the surface
of either a metallic or polymeric scaffolding with a polymeric
carrier that includes an active or bioactive agent or drug.
Polymeric scaffolding may also serve as a carrier of an active
agent or drug.
[0010] The stent must be able to satisfy a number of mechanical
requirements. The stent must have sufficient radial strength so
that it is capable of withstanding the structural loads, namely
radial compressive forces imposed on the stent as it supports the
walls of a vessel at the expanded target diameter. Radial strength,
which is the ability of a stent to resist radial compressive
forces, relates to a stent's radial yield strength and radial
stiffness around a circumferential direction of the stent. A
stent's "radial yield strength" or "radial strength" (for purposes
of this application) may be understood as the compressive loading,
which if exceeded, creates a yield stress condition resulting in
the stent diameter not returning to its unloaded diameter, i.e.,
there is irrecoverable deformation of the stent. When the radial
yield strength is exceeded the stent is expected to yield more
severely and only a minimal force is required to cause major
deformation.
[0011] Once expanded, the stent must adequately provide lumen
support during a time required for treatment in spite of the
various forces that may come to bear on it, including the cyclic
loading induced by the beating heart. In addition, the stent must
possess sufficient flexibility with a certain resistance to
fracture.
[0012] Stents made from biostable or non-erodible materials, such
as metals, have become the standard of care for percutaneous
coronary intervention (PCI) as well as in peripheral applications,
such as the superficial femoral artery (SFA). Such stents have been
shown to be capable of preventing early and later recoil and
restenosis. These permanent stents include bare metal stents and
drug eluting stents which include a metallic base or scaffold with
a polymer and drug coating.
[0013] In order not to affect healing of a diseased blood vessel,
the presence of the stent is necessary only for a limited period of
time. There are certain disadvantages to the presence of a
permanent implant in a vessel such as compliance mismatch between
the stent and vessel and risk of embolic events such as late stint
thrombosis. To alleviate such disadvantages, a stent can be made
from materials that erode or disintegrate through exposure to
conditions within the body. Thus, erodible portions of the stent
can disappear from the implant region after the treatment is
completed, leaving a healed vessel. Stents fabricated from
biodegradable, bioabsorbable, bioresorbable, and/or bioerodable
materials such as bioabsorbable polymers can be designed to
completely erode only after the clinical need for them has
ended.
[0014] Polymers tend to have a lower strength on a per unit weight
or volume basis than metals. As a result, the thickness of
structural members or struts of a polymer scaffold tends to larger
that metal stents. For example, a polymer scaffold for coronary
applications may have a thickness, width, or both greater than 100
microns, greater than 120 microns, 100-200 microns, 120-180,
130-170, or 140-160 microns. Metallic stent struts may have a
thickness, width, or both less than 100 microns, less than 80
microns, or 60 to 80 microns.
[0015] When a scaffold or stent is implanted, the struts of the
stent project into the blood vessel. Since the struts project into
the flow path of blood, the struts can create a resistance to and
disrupt blood flow. Cumulative evidence, derived from intravascular
ultrasound-based studies, has demonstrated a strong association
between local endothelial shear stress (ESS) patterns and
neointimal formation in bare metal stents, whereas in drug eluting
stents there is contradictory data about the effect of ESS on
vessel wall healing process. The effect of ESS on neointimal
development following a bioresorbable scaffold implantation has
remained unclear.
SUMMARY OF THE INVENTION
[0016] Embodiments of the invention include a method of treating
vascular disease in a patient comprising: deploying a bioabsorbable
polymer scaffold composed of a plurality of struts at a section or
segment of an artery of a patient, the polymer scaffold expanding
during deployment which expands the segment to a target diameter
such that struts of the scaffold are apposed on a wall of the
segment, wherein immediately upon deployment the struts disrupt
flow of blood through the segment resulting in recirculation zones
upstream and downstream of the struts that are in gaps between
struts, wherein the recirculation zones are exposed to a low shear
stress from the blood flow less than 1 Pa for at least 60% of a
surface of the struts and luminal surfaces of the struts are
exposed to a higher shear stress of at least 2 Pa, and wherein at
least one year after deployment neointimal formation is higher in
the recirculation zones than on the luminal surfaces of the struts.
In these embodiments, at least one year after deployment a mean of
the neointimal thickness is between 100 and 115 .mu.m and a
percentage volume obstruction of the a lumen of the segment by the
scaffold is less than 10%.
[0017] Embodiments of the invention include a method of treating
vascular disease in a patient comprising: expanding a bioabsorbable
polymer in a segment of an artery of a patient such that the
scaffold is expanded against a wall of the segment, wherein the
scaffold comprises a coating including a polymer and a drug and the
drug elutes from the coating into the artery, wherein flow of blood
past the scaffold through the segment results in regions of low
shear stress and regions of high shear stress immediately after the
expanding, wherein after at least 80% of the drug elutes from the
coating the regions of low shear stress promote neointimal
proliferation resulting in a negative or inverse correlation
between shear stress immediately after the expanding and the
neointimal proliferation at least one year after the expanding.
[0018] Embodiments of the present invention include a method of
treating vascular disease in a patient comprising: deploying a
bioabsorbable polymer scaffold composed of a plurality of struts at
a segment of an artery of a patient, the polymer scaffold expanding
during deployment which expands the segment to a target diameter
such that some of the struts of the scaffold are in contact with a
wall of the segment, wherein immediately after deployment at least
some of the struts are malapposed such that an abluminal surface of
the malapposed struts is not in contact with the wall of the
segment, wherein immediately upon deployment the malapposed struts
disrupt flow of blood through the segment resulting in
recirculation zones upstream and downstream of the struts that are
in gaps between the malapposed struts, wherein the recirculation
zones are exposed to a low shear stress from the blood flow less
than 1 Pa for at least 60% of a surface of the malapposed struts,
and wherein at least one year after deployment neointimal formation
is higher in the recirculation zones than on the luminal surfaces
of the struts.
[0019] The hemodynamic micro-environment appears to regulate
neointimal response following a bioresorbable scaffold (e.g., an
Absorb BVS) implantation. These findings underline the role of the
ESS patterns on vessel wall healing and may be taken into
consideration in the design of bioresorbable devices.
[0020] Several studies in the past have investigated the
association between local ESS patterns and neointimal formation in
bare metal and drug eluting stents. However, no study up to date
has evaluated the effect of ESS on neointimal development following
a bioresorbable scaffold implantation. The present application
discloses an analysis which investigates the impact of the local
hemodynamic environment on neointimal formation following a
bioresorbable vascular scaffold. The analysis is based on studies
of the Absorb BVS implantation in human patients.
[0021] The studies are based on twelve patients with an obstructive
lesion in a relatively straight arterial segment who were treated
with an Absorb BVS and had serial optical coherence tomographic
examination at baseline and 1 year follow-up were included in the
current analysis. The optical coherence tomographic data acquired
at follow-up were used to reconstruct the scaffolded segment. Blood
flow simulation was performed on the luminal surface at baseline
defined by the Absorb BVS struts and the estimated ESS was related
to the neointima thickness measured at 1 year follow-up.
[0022] At baseline the scaffolded segments were exposed to a
predominantly low ESS environment (61% of the measured ESS was
<1 Pa). At follow-up, the mean neointima thickness was 113.+-.45
.mu.m while the percentage scaffold volume obstruction was
13.1.+-.6.6%. A statistical significant inverse correlation was
noted between baseline logarithmic transformed ESS and neointima
thickness at 1 year follow-up in all studied segments (average:
-0.451, correlation coefficient range: -0.140 to -0.662). Mixed
linear regression analysis between baseline ESS and neointima
thickness at follow-up yielded a slope of -31 .mu.m/log(Pa) and a
y-intercept of 99 .mu.m.
[0023] A statistically significant inverse association was found
between ESS and NT in all the studied segments. These findings
underscore the role of the local hemodynamic milieu on neointimal
response and should be taken into consideration in the design of
bioresorbable devices.
[0024] Embodiments of the invention include a method of treating
vascular disease in a patient comprising: deploying a bioabsorbable
polymer scaffold composed of a plurality of struts at a segment of
an artery of a patient, the polymer scaffold expanding during
deployment which expands the segment to a target diameter such that
at least some of the struts of the scaffold are apposed on a wall
of the segment, wherein the bioabsorbable polymer scaffold
comprises an antiproliferative agent that elutes from the scaffold
upon deployment, wherein immediately upon deployment the struts
disrupt flow of blood through the segment resulting in
recirculation zones upstream and downstream of the struts, wherein
the recirculation zones are in gaps between the struts, wherein the
recirculation zones are exposed to a low shear stress from the
blood flow less than 1 Pa and luminal surfaces of the struts are
exposed to a higher shear stress of at least 2 Pa, and wherein
between deployment and one year after deployment neointimal
formation is higher in the recirculation zones than on the luminal
surfaces of the struts.
[0025] Embodiments of the any of the methods further include at
least one year after deployment a mean of the neointimal thickness
is between 100 and 115 .mu.m and a percentage volume obstruction of
the lumen of the segment is less than 10%; the low shear stress
regions comprise recirculation zones between struts and the high
shear stress regions comprise luminal surfaces of struts; the
recirculation zones are between struts that are embedded at least
50% in the wall; the recirculation zones are between struts
protruding at least 50% from the wall; the recirculation zones are
between struts not in contact with the wall; the thickness
(T)/width (W) is greater than 1.2; the thickness (T)/width (W) is
less than 0.8.
[0026] Embodiments of the invention include methods of treating
vascular disease in a patient comprising: expanding a bioabsorbable
polymer scaffold composed of a plurality of struts in a stenotic
segment of an artery of a patient such that the scaffold is
expanded against a wall of the segment, wherein the scaffold
comprises a coating including a polymer and an antiproliferative
drug and the drug elutes from the coating into the artery after the
expanding, wherein flow of blood past the scaffold through the
segment results in regions of low shear stress and regions of high
shear stress immediately after the expanding, wherein after at
least 80% of the drug elutes from the coating the regions of low
shear stress promote neointimal proliferation resulting in a
negative or inverse correlation between shear stress immediately
after the expanding and the neointimal proliferation at least one
year after the expanding.
[0027] Embodiments of the invention include methods of treating a
patient in need of treatment of coronary heart disease having a
stenotic segment of a coronary artery comprising: selecting a
bioabsorbable scaffold; identifying a negative or inverse
correlation or association between neointimal proliferation and
regions of low endothelial shear stress and high endothelial shear
stress of an endothelial shear stress pattern or distribution at a
segment or at a luminal surface the segment when the bioresorbable
scaffold is deployed at the segment; and creating the endothelial
shear stress pattern having the regions of low shear stress and
high shear stress in the segment when the bioresorbable scaffold is
deployed. The pattern or distribution may be immediately after
deployment. The inverse correlation develops as the neointimal
layer over and in between struts.
[0028] Embodiments of the invention include methods of treating a
patient in need of treatment of coronary heart disease having a
stenotic segment of a coronary artery comprising: selecting a
bioabsorbable scaffold that elutes an antiproliferative agent when
deployed; identifying a negative or inverse correlation or
association between neointimal proliferation and regions of low
endothelial shear stress and high endothelial shear stress of an
endothelial shear stress pattern or distribution of the
bioresorbable scaffold when deployed at the segment; and creating a
blood flow disturbance along the segment with regions of high
endothelial stress and regions of low endothelial shear stress when
the bioresorbable scaffold is deployed at the segment;
administering the antiproliferative agent to the segment from the
bioresorbable scaffold, wherein the neointimal proliferation
develops less than 1 year after deployment of the scaffold having a
negative or inverse correlation between endothelial shear stress at
deployment and neointimal thickness that develops after deployment;
and the endothelial shear stress distribution affects neointimal
formation such that there is increased neointima tissue in the
regions between the struts and minimal neointima over the struts
such as on the luminal surface of the struts such that the
neointimal thickness between the struts is greater than the
neointimal thickness over the luminal surface.
[0029] Embodiments of the invention include methods of treating a
patient in need of treatment of coronary heart disease having a
stenotic segment of a coronary artery comprising: determining
characteristics of a bioabsorbable scaffold that provides a
negative or inverse correlation between neointimal proliferation
and regions of low endothelial shear stress and high endothelial
shear stress of endothelial shear stress patterns at the segment
when the bioresorbable scaffold is deployed at the segment;
selecting a bioabsorbable scaffold based on the characteristics;
creating the endothelial shear stress pattern having the regions of
low shear stress and high shear stress in the segment when the
bioresorbable scaffold is deployed. Embodiments of any of the
methods may further include the characteristics are selected from
the group in any combination consisting of drug delivery
properties, strut thickness, strut width, ratio of strut thickness
to strut width and the drug delivery properties comprise type of
drug, dose of drug, coating polymer. The development of the
negative or inverse correlation may be between deployment and 3
months after deployment, between 3 and 6 months after deployment,
between 6 and 9 months after deployment, or between 9 months and 1
year after deployment. The development of the negative or inverse
correlation may be between 0 and 3 months, between 3 and 6 months,
or between 6 and 9 months after complete elution of
antiproliferative agent from the scaffold.
[0030] In any of the disclosed methods, the scaffold flow
disruption and drug delivery may provide for the formation of a
protective thin layer of neointimal tissue without restricting the
luminal dimensions, covers the underlying plaque and the scaffold
struts which minimizes the risk for late scaffold thrombosis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0032] FIG. 1A depicts an exemplary stent scaffold.
[0033] FIGS. 1B-C depict an exemplary scaffold.
[0034] FIG. 2 depicts optical coherence tomographic image acquired
at baseline (A) and the corresponding frame obtained at 1 year
follow-up showing the distal end of a scaffolded segment (the
distal marker is located at 11 o'clock) (B).
[0035] FIG. 3 depicts a longitudinal optical coherence tomographic
(OCT) view of a coronary segment implanted with an Absorb
bioresorbable scaffold (A).
[0036] FIG. 4 depicts a three dimensional reconstruction of
baseline luminal surface at the scaffolded segment.
[0037] FIG. 5 depicts a longitudinal section of a scaffolded
section demonstrating the blood flow streamlines with velocity
color coding.
[0038] FIG. 6A depicts regression curves showing the association
between the logarithmic transformed ESS at baseline and neointima
thickness at follow-up in the 12 segments included in the current
analysis.
[0039] FIG. 6B depicts linear regression analysis between the
logarithmic transformed ESS and neointima thickness for a typical
patient case.
INCORPORATION BY REFERENCE
[0040] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference, and as if each said individual publication or patent
application was fully set forth, including any figures, herein.
DETAILED DESCRIPTION OF THE INVENTION
[0041] Embodiments of the present invention include treatment of
coronary artery disease and peripheral artery disease with
bioresorbable polymer stents. The bioresorbable stents can include
a support structure in the form of a scaffold made of a material
that is bioresorbable, for example, a bioresorbable polymer such as
a lactide-based polymer. The scaffold may be made partially or
completely of a bioresorbable polymer. The scaffold may include
non-polymer and/or nonbiodegradable parts or additives. The
scaffold is designed to completely erode away from an implant site
after treatment of an artery is completed. The scaffold can further
include a drug, such as an antiproliferative or anti-inflammatory
agents. A polymer coating disposed over the scaffold can include
the drug which is released from the coating after implantation of
the stent. The polymer of the coating is also bioresorbable.
[0042] The treatment methods can apply to bioresorbable scaffolds
for both coronary and peripheral treatment. Bioresorbable polymer
scaffolds for coronary artery treatment can have a length between
12 to 18 mm. Such coronary scaffolds may be laser cut from polymer
tubes with a diameter between 2.5 mm to 4.5 mm and with a
thickness/width of 100-200 microns, or more narrowly, 140-160
microns. A bioresorbable polymer scaffold for peripheral treatment,
for example, SFA treatment is typically longer, a larger diameter,
and may have thicker struts than a coronary scaffold. For example,
the scaffolds may have a length 18 and 36 mm, 36 and 40 mm or even
between 40 and 200 mm. An SFA scaffold may be cut from tubing with
a diameter of between 5-10 mm, 6-8 mm and a wall thickness of about
greater than 150 microns, for example, 150 to 250 microns, 250 to
300 microns, 300 to 350 microns, 350 to 400 microns, or greater
than 400 microns.
[0043] The coronary scaffold may be configured for being deployed
by a non-compliant or semi-compliant balloon from about a 1.1 to
1.5 mm diameter (e.g., 1.35 mm) crimped profile. Exemplary balloon
sizes include 2.5 mm, 3.0 mm, 3.5 mm, and 4.0 mm, where the balloon
size refers to a nominal inflated diameter of the balloon. The
scaffold may be deployed to a diameter of between 2.5 mm and 5 mm,
2.5 to 4.5 mm, or any value between and including the endpoints.
The pressure of the balloon to deploy the scaffold may be 12 to 20
psi. Embodiments of the invention include the scaffold in a crimped
diameter over and in contact with a deflated catheter balloon.
[0044] The intended deployment diameter may correspond to, but is
not limited to, the nominal deployment diameter of a catheter
balloon which is configured to expand the scaffold. The balloon
pressure and the diameter to which the balloon inflates and expands
the scaffold may vary from deployment to deployment. For example,
the balloon may expand the scaffold in a range between the nominal
inflated diameter to the nominal inflated diameter plus 0.5 mm,
e.g., a 3.0 mm balloon may expand a scaffold between 3 and 3.5 mm.
In any case, the inflated diameter at deployment is less than the
rated burst diameter of the balloon.
[0045] A scaffold may be laser cut from a tube (i.e., a pre-cut
tube) that is less than or greater than an intended deployment
diameter. For example, a pre-cut tube diameter may be 0.7 to 1
times or 1 to 1.5 times the intended deployment diameter or any
value in between and including the endpoints.
[0046] The scaffolds and coating of the present invention may be
made of or include bioresorbable polymer including poly(L-lactide)
(PLLA), poly(D-lactide) (PDLA), polyglycolide (PGA),
poly(D,L-lactide (PDLLA), and poly(L-lactide-co-glycolide) (PLGA).
The PLGA include those having a mole % of (LA:GA) of 85:15 (or a
range of 82:18 to 88:12), 95:5 (or a range of 93:7 to 97:3), or
commercially available PLGA products identified being 85:15 or 95:5
PLGA. Additional bioresorbable polymers include but are not limited
to polyhydroxyalkanoates (PHA), poly(4-hydroxybutyrate) (P4HB),
poly(.epsilon.-caprolactone), (PCL) poly(trimethylene carbonate)
(PTMC), poly(butylene succinate) (PBS), poly(p-dioxanone) (PDO),
poly(ester amides) (PEA), and including copolymers (block, random,
alternating) and blends of any combination of polymers
disclosed.
[0047] The present invention is applicable to, but is not limited
to, self-expandable stents, balloon-expandable stents,
stent-grafts, and generally tubular medical devices in the
treatment of artery disease. The present invention is further
applicable to various stent designs including wire structures, and
woven mesh structures.
[0048] Self expandable or self expanding stents include a
bioabsorbable polymer scaffold that elastically expands to the
target diameter upon removal of an external constraint. The self
expanding scaffold expands to a larger diameter when an external
constraint is removed. This external constraint could be applied
with a sheath that is oriented over a compressed scaffold. The
sheath is applied to the scaffold after the scaffold has been
compressed by a crimping process. After the stent is positioned at
the implant site, the sheath may be retracted by a mechanism that
is available at the end of the catheter system and is operable by
the physician. The self expanding bioabsorbable scaffold property
is achieved by imposing only elastic deformation to the scaffold
during the manufacturing step that compresses the scaffold into the
sheath.
[0049] The bioabsorbable scaffold may also be expanded by a
balloon. In this embodiment the scaffold is plastically deformed
during the manufacturing process to tightly compress the scaffold
onto a balloon on a catheter system. The scaffold is deployed at
the treatment site by inflation of the balloon which expands the
scaffold. The balloon will induce areas of plastic stress in the
bioabsorbable material to cause the scaffold to achieve and
maintain the appropriate diameter on deployment.
[0050] A stent scaffold can include a plurality of cylindrical
rings connected or coupled with linking elements. For example, the
rings may have an undulating sinusoidal structure. When deployed in
a section of a vessel the cylindrical rings are load bearing and
support the vessel wall at an expanded diameter or a diameter range
due to cyclical forces in the vessel. Upon deployment, the scaffold
may recoil inward slightly, for example less than 5% or 10%. Load
bearing refers to the supporting of the load imposed by radial
inwardly directed forces. Structural elements, such as the linking
elements or struts, are generally non-load bearing, serving to
maintain connectivity between the rings. For example, a stent may
include a scaffold composed of a pattern or network of
interconnecting structural elements or struts.
[0051] FIG. 1A depicts a view of an exemplary stent 100. In some
embodiments, a stent may include a body, backbone, or scaffold
having a pattern or network of interconnecting structural elements
105. Stent 100 may be formed from a tube (not shown). FIG. 1A
illustrates features that are typical to many stent patterns
including undulating sinusoidal cylindrical rings 107 connected by
linking elements 110. As mentioned above, the cylindrical rings are
load bearing in that they provide radially directed force to
support the walls of a vessel. The linking elements generally
function to hold the cylindrical rings together. A structure such
as stent 100 having a plurality of structural elements may be
referred to as a stent scaffold or scaffold. Although the scaffold
may further include a coating, it is the scaffold structure that is
the load bearing structure that is responsible for supporting lumen
walls once the scaffold is expanded in a lumen.
[0052] The structural pattern in FIG. 1A is merely exemplary and
serves to illustrate the basic structure and features of a stent
pattern. A stent such as stent 100 may be fabricated from a
polymeric tube or a sheet by rolling and bonding the sheet to form
the tube. A tube or sheet can be formed by extrusion or injection
molding. A stent pattern, such as the one pictured in FIG. 1A, can
be formed on a tube or sheet with a technique such as laser cutting
or chemical etching. The stent can then be crimped on to a balloon
or catheter for delivery into a bodily lumen. Exemplary scaffolds
are disclosed in U.S. Patent Publication No. 2008-0275537.
[0053] Methods of treating coronary heart disease may include
identifying a segment of a blood vessel that is stenotic in a
patient in need of treatment of coronary heart disease (CAD) and
expanding the segment to a reference vessel diameter through
implantation of a bioresorbable scaffold at the segment. The method
may further include releasing drug from the scaffold for up to 2 to
3 months after the expanding to control neointimal proliferation to
reduce narrowing of the segment due to smooth cells that
proliferate and form a neointima layer at a surface of a wall of
the segment. The scaffold may provide support to the segment at an
expanded diameter for less than 6 months after deployment. A
compliance of the supported segment is dominated by a compliance of
the scaffold which is less than a natural compliance of a blood
vessel. The vessel wall of the segment may be remodeled during the
supporting so that an increased diameter is maintained after the
supporting when a radial strength of the scaffold decreases due to
biodegradation of the scaffold. The increased diameter allows for
increased blood flow compared to the stenotic segment. An
endothelial or neointimal layer is formed that incorporates or
covers the scaffold within 4 to 6 months of implantation of the
scaffold. The compliance of the remodeled segment may be restored
to the natural compliance of a blood vessel through the decrease in
the radial strength of the scaffold, loss of connectivity between
struts of the scaffold, and erosion of the scaffold from the
segment. Vasomotion may be restored to the remodeled segment as the
compliance is restored that of a healthy blood vessel.
[0054] The stenotic segment, for example, may be a single denovo
stenotic lesion with a diameter stenosis that is 50% or more.
Restoring vasomotion may correspond to vasodilation of at least 3%
of a mean luminal diameter of the remodeled segment. The segment
may be supported for 1 to 4 months after the increasing. Some
treatments may include increasing of at least one of mean lumen
area, minimal lumen area, and lumen volume between the 6 months and
2 years after deployment as the radial strength decreases, as the
connectivity between struts of the scaffold is lost, and as the
scaffold erodes from the segment. Further details of treatment may
be found in US 2010/019833.
[0055] The ABSORB Bioresorbable everolimus eluting vascular
scaffold (ABSORB BVS) of Abbott Vascular Inc. of Santa Clara,
Calif. was recently developed to provide an approach to treating
coronary artery lesions with transient vessel support and drug
delivery. Preclinical evaluation in an animal model demonstrated
substantial polymer degradation at 2-years post ABSORB BVS
implantation, with complete disappearance of the BVS strut
"footprint" in the vessel wall within a 3-4 year period. The first
generation BVS (BVS revision 1.0) was tested in the ABSORB cohort A
trial and demonstrated promising results with a low event clinical
rate at up to 4 years follow up (EuroIntervention 2012;
7:1060-1061). The device was however limited by a slightly higher
acute recoil compared to conventional metallic platform stents.
[0056] Improvements in design were therefore introduced in the
second generation BVS (BVS revision 1.1), notably an enhanced
mechanical strength, more durable support to the vessel wall, a
reduced maximum circular unsupported surface area and a more
uniform strut distribution and drug delivery. The performance of
the next generation BVS revision 1.1 was subsequently investigated
in the ABSORB Cohort B Trial which reported excellent clinical
results at 1 and 2 year follow-up (J Am Coll Cardiol. 2011; 58:
B66).
[0057] FIGS. 1B-C depicts the BVS revision 1.1 scaffold. FIG. 1B
shows the scaffold in a crimped configuration. FIG. 1C show a
cross-section of a strut showing the polymer backbone or core of
the strut surrounded by a drug/polymer matrix. The cross-section of
the strut has an abluminal surface or side that faces the vessel
wall and a luminal surface or side that faces the lumen of the
vessel. The strut cross-section shown is rectangular with rounded
corners with a width (W) and thickness T. The BVS revision 1.1
scaffold is approximately square with an aspect ratio T/W close to
1.
[0058] The polymer backbone is made of poly(L-lactide). The
diameter of the scaffold in an as-fabricated or pre-crimped
configuration is 3 mm and the length is 18 mm. The struts may have
a width of about 165 microns and thickness of about 152 microns,
for example, 156 microns. The coating is a mixture of
poly(DL-lactide) and everolimus with a 1:1 ratio of polymer to
drug. The coating is about 2 to 2.5 microns in thickness.
[0059] In general, the treatment with bioabsorbable polymer stents
has a number of advantages over permanent implants: (i) The stent
disappears from the treated site resulting in reduction or
elimination of late stent thrombosis; (ii) disappearance of the
stent facilitates repeat treatments (surgical or percutaneous) to
the same site; (iii) disappearance of the stent allows restoration
of vasomotion at the treatment site (the presence of a rigid
permanent metal stent restricts vasomotion); (iv) the
bioabsorbability results in freedom from side-branch obstruction by
struts; (v) the disappearance results in freedom from strut
fracture and ensuing restenosis. Some of these advantages may be
relevant to improving clinical outcomes for diabetic patients.
[0060] In the short term and over the long term, a bioresorbable
scaffold has the advantage of being less traumatic to the vessel
wall. Since the bioresorbable scaffold degrades with time and
eventually disappears, trauma associated with the presence of a
scaffold decreases with time and eventually disappears.
[0061] Neointimal formation is modulated by several factors
including the vessel wall trauma caused during stent deployment,
the plaque burden, the composition of the underlying plaque, as
well as local endothelial shear stress (ESS) patterns (e.g.,
Hoffmann, et al., J Am Coll Cardiol 1998; 31:43-9). Several
clinical and experimental studies have provided evidence that local
hemodynamic factors, in particular low ESS, promote neointimal
formation in bare metal stents whereas in drug eluting stents the
association between ESS and neointimal proliferation is weak and
appears to be affected by the mechanisms of action and probably the
release kinetics of the eluted drug (e.g., Papafaklis, JACC
Cardiovasc Interv 2010; 3:1181-9).
[0062] Bioresorbable scaffold is a new technology introduced to
overcome the long term implications of metallic caging as these
devices have the unique ability to disappear after implantation,
allowing restoration of vessel physiology (Serruys, Eur Heart J
2012; 33:16-25b). The first clinical studies provided evidence
about the safety and efficacy of these devices and revealed a
gradual increase of the neointima tissue which, however, was
accommodated by the expanding scaffold and did not appear to affect
luminal dimensions (Ormiston et al., Circ Cardiovasc Interv 2012;
5:620-32). It has been demonstrated that neointima tissue has an
asymmetric distribution around the circumference of the vessel wall
indicating that local factors (i.e., vessel wall trauma, increased
plaque inflammation and local hemodynamics) are likely to be
involved and regulate this process (Brugaletta et al., 2012;
221:106-12).
[0063] The aim of the present invention and the associated analysis
is the impact of ESS on neointima proliferation following a
bioresorbable vascular scaffold implantation. In contrast to
previous reports optical coherence tomographic (OCT) data it
utilized to reconstruct the surface of the scaffolded segment at
baseline, simulate blood flow and assess vessel wall healing.
"Baseline" refers to the time point immediately after the stent is
deployed in the vessel, and if the stint is balloon expandable,
after the balloon is removed from the implant site. The high
resolution of this imaging technique allows more detailed
reconstruction of luminal morphology and evaluation of the
hemodynamic micro-environment following device implantation and its
impact on neointimal growth.
[0064] Data was analyzed from patients recruited in the second
group of the ABSORB Cohort B Trial (A Clinical Evaluation of the
Everolimus Eluting Bioresorbable Vascular Scaffold System in the
Treatment of Patients with de Novo Native Coronary Artery Lesions)
(NCT00856856). The study design has already been described in
detail by Serruys et al. Circulation 2010; 122:2301-12. In brief,
101 patients with single or two vessel de novo coronary disease
implanted with an Absorb BVS (Abbott Vascular, Santa Clara, Calif.,
USA) (dimensions: 3.0.times.18 mm) were included in this
prospective multicenter trial. The studied population was divided
in two groups. Both groups had serial angiographic, grayscale
intravascular ultrasound (IVUS), IVUS virtual histology and OCT
evaluation at three time points. The first group (B1) had these
tests at baseline post device implantation, 6 months and 2 years
follow-up, while the second group (B2) had these investigations at
baseline, 1 year and 3 years follow-up. The current analysis
included only the patients from Cohort B2 who had received an
Absorb BVS in a relatively straight coronary segment and had
undergone OCT evaluation at baseline and 1 year follow-up.
[0065] Coronary reconstruction was performed using only the OCT
data neglecting the vessel curvature. To minimize the error
introduced by this approximation relatively straight arterial
segments were analyzed. The angulation of the treated segments was
assessed using a previously described methodology (Gomez-Lara et
al., JACC Cardiovasc Interv 2010; 3:1190-8). In brief, in an
angiographic view with minimal foreshortening and overlapping we
measured the angulation of the treated segment--extended from the
nearest proximal to the implanted lesion side branch to the nearest
distal side branch--by estimating the angle defined by the tangents
of the centerlines of the 5 mm proximal and distal portions of the
analyzed segment. The cutoff value used to categorize straight and
curved segments in the current analysis was the mean+2 standard
deviations (29 degrees) of the angulations measured during balloon
inflation in all the segments treated in the Absorb Cohort B study
(Gomez-Lara et al.).
[0066] OCT image acquisition was performed at baseline (immediately
after scaffold implantation) and at 1 year follow-up using a C7XR
Fourier Domain system (Lightlab Imaging, Westford, Mass., USA). The
data acquired at baseline were analyzed by two expert
observers--blinded to patients' procedural and clinical
characteristics--who reviewed the scaffolded segment and identified
in each frame the embedded, the protruded, and the malapposed
struts. Embedded struts were struts of which their surface was
greater than 50% impacted into the vessel wall. Struts were
considered protruded when they were in contact with the vessel wall
but with less than 50% of their surface being impacted into the
vessel wall. Struts were considered malapposed when the struts were
such that their abluminal surface was not in contact with the
vessel wall. The feasibility of this classification has already
been tested and the reported results have shown a high
inter-observer agreement (K index: 0.75) (Gomez-Lara et al., JACC
Cardiovasc Interv 2011; 4:992-1001).
[0067] The existence of and the degree of embedding, protrusion,
and malapposition can depend on the shape and degree of narrowing
of the vessel wall at the implant site. The existence of and the
degree of embedding, protrusion, and malapposition can also depend
on the deployment diameter and balloon pressure. For example, the
scaffold may be deployed at some value greater than the nominal
inflated diameter of the balloon.
[0068] Incomplete apposition can occur at intervention (deployment)
and persist for several months. Additionally, stent struts can
dislodge from complete apposition with the vessel wall after
intervention and is referred to as late-acquired stent apposition
(LAISA). U.S. Patent Application No. 2010/0198331. For example, the
struts may dislodge 1, 2, 3, 4 months after intervention or 1 to 5,
1 to 2, 2 to 3, 3 to 4, or 4 to 5 months after intervention. In
either case, the struts can disrupt blood flow and cause high and
low shear stress regions as described. It is expected that the
negative or inverse correlation between ESS and neointimal
proliferation will occur for both types of dislodged struts.
[0069] The regions between struts can be between any combination of
embedded, protruding, or malapposed struts. It is expected that the
ESS will vary between the different combinations and result in
different degrees of neointimal proliferation in the regions and on
top of the struts.
[0070] FIG. 2 depicts optical coherence tomographic image acquired
at baseline (A) and the corresponding frame obtained at 1 year
follow-up showing the distal end of a scaffolded segment (the
distal marker is located at 11 o'clock) (B). The green line in
panel C corresponds to the luminal border at baseline as defined in
the follow-up frame, whereas the blue line defines the scaffold
perimeter, the gravitational center of which was used for the
correct placement of the detected borders on the vessel backbone.
The two observers were able to identify four corresponding struts
in the baseline and follow-up frames two of which (strut 3 and 4)
were embedded at baseline. It was not possible to identify
corresporidence for four struts (indicated with an asterisk) at the
frame acquired at follow-up. The area between the luminal border at
baseline (green line) and the luminal border at follow-up up (red
line) corresponds to the neointima tissue that is portrayed in
Panel D in a semi-transparent fashion. In a second case example
strut malapposition (strut 1) was noted in two corresponding OCT
images acquired at baseline (E) and 1 year follow-up (F). In this
location the baseline and follow-up luminal border as well as the
scaffold perimeter is defined by the endoluminal side of the
neointima (G, H).
[0071] The data acquired at 1 year follow-up were used to
reconstruct two surfaces: 1) the luminal surface at baseline post
scaffold implantation and 2) the luminal surface at 1 year
follow-up. In each follow-up OCT examination the observers
identified the frames portraying, the scaffolded segment and
analyzed 1 frame at every 0.4 mm interval in the non-scaffolded
segment and 1 frame at 0.2 mm interval in the scaffolded segment.
The luminal morphology at baseline was approximated by the luminal
borders in the non-scaffolded segment at 1 year follow-up. In the
scaffolded segment the observers identified corresponding struts
between baseline and follow-up OCT examinations and in case that
the baseline struts were embedded the baseline luminal borders were
defined by splines connecting the adluminal sides of the struts
(portrayed at the frames acquired at 1 year follow-up), whereas in
case that the baseline struts were protruded or malapposed the
baseline luminal borders was defined by the adluminal sides of the
struts (portrayed at the frames acquired at 1 year follow-up) and
between struts by the segment connecting the abluminal sides of
adjacent struts (FIG. 2). For the struts that were not possible to
identify correspondence between baseline and follow-up
examinations, we assumed that these struts were protruded since the
majority of the struts were protruded at the baseline examination
(Gomez-Lara et al., JACC Cardiovasc Interv 2011; 4:992-1001).
[0072] The luminal surface at follow-up was constructed by the
luminal borders in the scaffolded segment defined by the
endoluminal borders of the neointima. Malapposed struts at 1 year
follow-up were not taken into consideration and in these segments'
the baseline luminal border was approximated by the endoluminal
border of the neointima (FIG. 2). Segments exhibiting extensive
malapposition (malapposition seen in >25.sup.iof the scaffolded
segment) were excluded from the analysis.
[0073] FIG. 3 depicts longitudinal optical coherence tomographic
(OCT) view of a coronary segment implanted with an Absorb
bioresorbable scaffold (A). An eccentric calcified plaque (white,
left-most arrow) noted at the proximal edge of the scaffold. The
arrows indicate changes in the position of the OCT catheter with
regards the lumen wall (initially the OCT catheter was closer to
the upper border, then to the low border and finally to the upper
border). These changes are due to the three dimensional (3D)
geometry of the vessel, the vessel motion during the cardiac circle
and plaque protrusion into the lumen. Panel B shows the
reconstructed artery with the endothelial shear stress (ESS)
portrayed in the 3D surface with the use of a-color coded map (low
ESS corresponds to the blue and high to the red color). In contrast
to the model showed in Panel B the model portrayed in Panel C was
obtained after positioning the detected borders on the vessel
backbone using the gravitational center of the luminal borders in
the non-scaffolded segment and the scaffold in the scaffolded
segment. It is apparent that the change in the vessel geometry has
an impact on the ESS distribution especially in segments with
eccentric-protruded plaques (white arrow) and increased curvature.
Although this approach is likely to distort the real geometry of
the model when eccentric plaques are present it is expected to give
more accurate reconstruction in the scaffolded segment where the
scaffold is anticipated to be symmetrically expanded and have a
round-shaped morphology.
[0074] The vessel centerline was approximated by a straight segment
with a length equal to the length of the studied coronary and
divided into equidistant sub-segments corresponding to the number
of the OCT frames. To minimize the error introduced by the lateral
displacement of the OCT catheter in the coronary artery during
pull-back (caused by the lateral movements of the coronary artery
during the cardiac circle) the gravitational centers of the luminal
borders in native segments were estimated, and of the scaffold
(defined by the abluminal side of the scaffold) in scaffolded
segments, and used them for placing the detected borders onto the
vessel centerline. In particular each border was placed
perpendicularly onto the corresponding sub-segment in such a way so
that the relevant gravitational center is located in the middle of
the sub-segment (FIG. 3). This approach is likely to distort the
anatomy of eccentric lesions located proximally or distally to the
scaffold but, on the other hand, it is expected to provide a more
accurate representation of the coronary morphology in the
scaffolded segment and eliminate the wave-like artifacts introduced
by the movement of the catheter (during the cardiac circle) which
can affect the ESS measurements (FIG. 3).
[0075] The final outcome of this process is two non-uniform
rational B-spline surfaces: the first representing the luminal
surface at baseline (constructed by the luminal borders in the
non-scaffolded segment and by the scaffold borders in the
scaffolded segment) and the second represented the luminal surface
at 1 year follow-up (constructed by the luminal borders in the
scaffolded segment).
[0076] The obtained geometries were further processed with
computational fluid dynamics techniques for the generation of a
finite volume mesh. Anisotropic meshes with unstructured
tetrahedral elements were generated for each baseline surface using
an automated mesh generation program (ICEM CFD, Ansys, Canonsburg,
Pa.). To capture the detailed characteristics of the hemodynamic
micro-environment, mesh density was increased around the stent
struts and within the boundary layer of the flow field, and had a
maximum element edge equal to approximately 1/4 of the BVS strut
thickness (i.e., .about.40 .mu.m). Blood flow simulation was
performed by solving the 3D Navier-Stokes equations (CFX 11,
Ansys). Blood was considered as a homogeneous, Newtonian fluid with
a dynamic viscosity of 0.0035 Pas and a density of 1,050
kg/m.sup.3. Blood flow was modeled to be laminar and incompressible
with a steady flow profile at the inlet of the reconstructed
segment. Coronary blood flow for each artery was estimated by
measuring in two angiographic projections--obtained at baseline,
post scaffold implantation the number of frames required for the
contrast agent to pass from the inlet to the outlet of the
reconstructed segment, the volume of the segment at baseline and
the cine frame rate. The arterial wall was considered to be rigid
and no-slip conditions were applied at the baseline luminal
surface, while zero pressure conditions were imposed at the outlet.
ESS at baseline luminal surface was calculated as the product of
blood viscosity and the gradient of blood velocity at the wall.
[0077] In the scaffolded segment, the lumen volume at baseline and
1 year follow-up was estimated and the neointimal volume was
defined as: lumen volume at baseline-lumen volume at follow-up
whereas the percentage volume obstruction as: 100.times. neointima
volume/lumen volume at baseline. Neointimal thickness (NT) was
calculated as the distance between the luminal surface at baseline
and the luminal surface at follow-up using an in-house developed
algorithm implemented in Visual Fortran (Compaq Computer
Corporation, Houston, Tex.) (Papafaklis et al., Int J Cardiol 2009;
134:25-32). Positive values corresponded to areas of neointimal
hyperplasia. NT was measured along the axial direction per 0.2 mm
and around the vessel circumference per 5.degree. for each cross
section and was associated to ESS at the corresponding location.
Segments within the scaffold located at the origin of side branches
and their adjacent segments with length equal to the diameter of
the side branch were excluded from the analysis since the branches
were not included in the 3D reconstruction, and thus ESS assessment
in these areas is not considered to be reliable.
[0078] Continuous variables are presented as mean.+-.standard
deviation whereas categorical as counts and percentages. Pearson
correlation coefficient and linear regression analysis were
implemented to investigate the association between the logarithmic
transformed ESS and the estimated NT at follow-up. To control
patient effect, a mixed model with random intercept and slope was
used to estimate the overall association between the logarithmic
transformed ESS and NT. In this mixed model, the autoregressive
covariance structure was utilized to take into consideration of the
nested structure of cross-sections within subjects.
[0079] The interobserver agreement in the identification of
corresponding struts between baseline and follow-up examination was
evaluated with the use of the Cohen's kappa test. A P value
<0.05 was considered statistical significant. Statistical
analysis was performed with the SPSS statistical software package
(version 18.0 for Windows, SPSS, Inc, Chicago, Ill.).
[0080] Twenty one patients (22 lesions) from Cohort B2 were
investigated with OCT at baseline and 1 year follow-up. In 14
patients (14 arteries) the treated segments had angulation
<29.degree.. Two cases were excluded from the analysis: the
first because of extensive malapposition and the second because of
poor OCT image quality. Thus 12 segments were reconstructed. The
baseline characteristics of the studied population are shown in
Table 1. Most of the patients suffered from hypercholesterolemia
(58%) and had hypertension (67%) and 83% were treated for stable
angina.
TABLE-US-00001 TABLE 1 Baseline characteristics of the studied
population. Studied population (n = 12) Baseline characteristics
Age (years) 61 .+-. 9 Male 8 (67%) Hypertension 8 (67%)
Hypercholesterolemia 7 (58%) Diabetes mellitus 0% (0) Current
smoking 4 (33%) Prior percutaneous coronary intervention 1 (8%)
Prior myocardial infarction 2 (17%) Stable angina 10 (83%) Unstable
angina 1 (8%) Silent ischemia 0 (0%) Treated vessel Left anterior
descending artery 9 (75%) Left circumflex artery 2 (17%) Right
coronary artery 1 (8%) Ramus intermedious 0 (0) Medications
.beta.-blockers Renin-angiotensin aldosterone inhibitors
Statins
[0081] The length of the reconstructed segments was 47.6.+-.110.5
mm whereas the length of the scaffolded segment was 19.6.+-.0.8 mm.
Neointimal proliferation was evident in all treated segments that
resulted in a percentage scaffold volume obstruction of
13.1.+-.6.6% (Table 2). The mean NT derived from the measurements
in the 12 patients (patient level analysis) was 113-45 .mu.m
(range: 72-200 .mu.m).
[0082] In general, the mean neointima thickness may be between 90
and 120 .mu.m, 100 and 115 .mu.m, or 100 and 110 .mu.m while the
percentage scaffold volume obstruction may be less than 5%, less
than 10%, less than 15%, or less than 20%. The mean neointima
thickness may be between 90 and 120 .mu.m, 100 and 115 .mu.m, 100
and 110 .mu.m, 110 and 115 .mu.m while the percentage scaffold
volume obstruction may be less than 5%, less than 10%, less than
15%, less than 20%, 5 to 10%, 10 to 15%, 15 to 20%, or 5 to 20% for
any of the scaffolds disclosed herein. Any combination of scaffolds
disclosed, mean intimal thickness, and volume obstruction is
disclosed.
TABLE-US-00002 TABLE 2 Quantitative analysis of the scaffolded
segment in the 3 dimensional reconstructed arteries. Studied
population (n = 12) Baseline mean lumen area (mm.sup.2) 6.70 .+-.
1.35 Follow-up mean lumen area (mm.sup.2) 5.85 .+-. 1.43 Mean
neointima tissue area (mm.sup.2) 0.85 .+-. 0.38 Mean neointima
thickness (.mu.m) 113 .+-. 45 Lumen volume at baseline (mm.sup.3)
130.9 .+-. 25.7 Lumen volume at follow-up (mm.sup.3) 114.6 .+-.
28.2 Neointima tissue volume (mm.sup.3) 16.4 .+-. 6.9 Percentage
volume obstruction (%) 13.1 .+-. 6.6
[0083] Methods of treatment of a patient having coronary heart
disease include identifying a bioabsorbable polymer scaffold
composed of a plurality of struts for deploying at a stenotic
segment of an artery of the patient, such that the scaffold expands
the segment to a target diameter such that at least some of the
struts of the scaffold are apposed on a wall of the segment. The
method may include identifying blood flow regions past the struts
that have higher neointimal formation and regions that have lower
neointimal formation at follow-up-times post-deployment. The method
further includes identifying blood flow regions past the struts
that have lower shear stress and blood flow regions that have
higher shear stress at the time of deployment. The method further
includes associating the regions of higher neointimal formation
with the lower shear stress regions and the regions of lower
neointimal formation with the high shear stress regions. The
scaffold is then provided for deployment in the patient followed by
deployment in the patient.
[0084] The lower shear stress regions may be identified as
recirculation zones upstream and downstream of the struts that
correspond to gaps between the struts wherein immediately upon
deployment the struts disrupt flow of blood through the segment.
The higher shear stress regions may be identified as the luminal
surfaces of the struts. The recirculation zones may be exposed to a
low shear stress from the blood flow less than 1 Pa and luminal
surfaces of the struts may be exposed to a higher shear stress
which may be greater than 1 Pa or 2 Pa. The follow-up time may be
identified as at least 3 months, 6; months, 1 year, 3 to 6 months,
or 6 months to 1 year. The struts corresponding to the regions may
be identified as malapposed struts.
[0085] FIG. 4 depicts a three dimensional reconstruction of
baseline luminal surface at the scaffolded segment. Panel (A)
illustrates the endothelial shear stress (ESS) distribution in the
scaffolded segment portrayed in a color-coded map (with the red
color indicating high shear stress and the blue low shear stress)
and (B) the corresponding neointima thickness. The dash lines in
panel A and B indicate the location of the optical coherence
tomographic images 1 and 2 in the reconstructed segment. Panel 1'
and 2' show the ESS distribution at baseline across the
circumference of the vessel wall and panel 1'' and 2'' the
neointima thickness portrayed in a semi transparent fashion. As it
is shown in panels i, ii, iii the ESS is low in the between the
struts areas and high on the top of the struts. The neointima
tissue appears increased in segments with low ESS and reduced in
segments with high ESS values.
[0086] FIG. 5 depicts a longitudinal section of a scaffolded
section demonstrating the blood flow streamlines with velocity
color coding. The endothelial shear stress (ESS) distribution along
the baseline luminal surface is portrayed in a color coded map,
whereas the neointima thickness at 1 year follow-up is shown in a
semitransparent fashion. Low velocities and ESS, as well as
recirculation zones are noted in the inter-strut areas or regions,
whereas ESS values are high on the top of the struts, i.e., on or
around the luminal surface of the struts. The ESS distribution
appears to affect neointimal formation, as there is increased
neointima tissue in the regions between the struts and minimal
neointima over the struts, particularly the luminal surface of the
struts.
[0087] In general, the ESS values at the top of a strut, i.e., the
luminal surface, for a bioresorbable scaffold may be greater than 1
Pa, 1.2 Pa, 1.5 Pa, or 2 Pa. The ESS values may be 1 to 2 Pa, 1.2
to 2 Pa, or 1.2 to 2 Pa.
[0088] In the 12 patients (patient level analysis) the mean ESS
measured in the scaffolded segments at baseline was 1.10.+-.0.35
Pa. Cross sectional level analysis showed that 61% of the computed
ESS were <1 Pa. As it is shown in FIG. 4 the protruded struts
created a rough luminal surface at baseline that affected the local
hemodynamic micro-environment. Flow recirculation zones were noted
proximally and distally to the protruded struts resulting in low
ESS in these regions and relatively high ESS on the top of the
struts (FIG. 5). The low ESS noted in these areas appeared to have
affected neointima formation with an increased tissue formation
proximally and distally to the scaffold struts and limited
neointima formation on the top of the struts (FIGS. 4 and 5).
[0089] A negative correlation coefficient (average: -0.451;
statistically different from 0) was noted between ESS at baseline
and logarithmic transformed NT at 1 year follow-up in all patients
(P<0.001). Table 3 provides the correlation coefficients between
the logarithmic transformed baseline ESS and the NT for each
subject, as, well as the estimated slopes and y-intercepts after
applying linear regression analysis for each subject (FIG. 5). The
linear mixed-effect model yielded an overall slope of -31
.mu.m/log(Pa) and y-intercept of 99 .mu.m.
[0090] FIG. 6A depicts regression curves showing the association
between the logarithmic transformed ESS at baseline and neointima
thickness at follow-up in the 12 segments included in the current
analysis. FIG. 6B depicts linear regression analysis between the
logarithmic transformed ESS and neointima thickness for a typical
patient case.
TABLE-US-00003 TABLE 3 Correlation coefficient, slope and
y-intercept obtained after applying linear regression analysis
between logarithmic transformed baseline ESS and neointimal
thickness at 1 year follow-up in each patient case. Patient-
Correlation- Slope- y-intercept- number coefficient (.mu.m/(log)Pa)
(.mu.m) 1 -0.480 -30 116 2 -0.412 -37 181 3 -0.140 -35 206 4 -0.426
-26 57 5 -0.386 -28 84 6 -0.488 -29 85 7 -0.533 -31 69 8 -0.590 -34
65 9 -0.662 -39 122 10 -0.410 -24 58 11 -0.428 -33 72 12 -0.455 -30
68
[0091] The reliability of the two observers in identifying
corresponding struts between baseline and the follow-up
examinations was examined in 100 frames randomly selected from 8
patients. The Kappa index was 0.79 indicating a good agreement.
[0092] In the presently described study serial OCT data, for the
first time, and computational fluid dynamics techniques were used
to evaluate the effect of the hemodynamic micro-environment on
neointimal formation post implantation for a bioresorbable scaffold
(Absorb BVS). It was found that 1) the thick protruded struts
(strut thickness: 156 .mu.m) of the implanted scaffold create a
rough surface which causes flow disturbance and recirculation zones
resulting in low ESS and 2) that the reported low ESS contributed
to neointimal formation as there was a negative correlation in all
the studied segments between ESS and NT.
[0093] Several computational experimental and clinical reports in
the past have examined the effect of stent implantation on local
hemodynamics and the association between ESS and neointimal
formation. In silico blood flow simulation studies have underscored
the effect of stent design on local hemodynamic patterns with the
stents having thick rectangular-shaped struts to cause flow
disruption and lead to a low ESS environment, whereas the devices
with thin circular-shaped struts appear to minimally influence the
local flow and ESS (e.g., Duraiswamy et al., 2009; 131:061006).
Clinical studies in 3D models obtained from patient data have shown
an inverse correlation between ESS and NT in bare metal stents,
whereas in drug eluting stents there are conflicting reports (e.g,
Gijsen et al., Am J Cardiol 2003; 92:1325-8). Gijsen et al
demonstrated an inverse relation between ESS and neointimal
formation in patients treated with sirolimus eluting stents,
whereas Suzuki et al found that ESS had no impact on neointimal
development in diabetic patients implanted with the same type of
stent. Papafaklis et al evaluated the association between
neointimal formation and ESS in 10 patients implanted with
paclitaxel eluting stents and 10 patients treated with sirolimus
eluting stents, and found an inverse correlation between ESS and NT
in the paclitaxel arm, but no significant association in the group
of patients implanted with sirolimus eluting stents, advocating
that these findings are due to the different pathophysiological
effect of each drug on vessel wall healing and the pro-restenotic
ESS biological pathway (Papafaklis, JACC Cardiovasc Interv 2010;
3:1181-9). However, a significant limitation of the abovementioned
studies is the fact that neointimal formation was measured assuming
that stent struts were well apposed post device implantation and
that coronary reconstruction was based on IVUS, an imaging modality
with a limited radial resolution which cannot accurately evaluate
the lumen surface irregularities caused by the stent struts and the
modest neointima proliferation in drug eluting stents.
[0094] The study disclosed herein overcame the abovementioned
pitfalls as it uses for the first time OCT to reconstruct the
coronary lumen. OCT with its high radial resolution allows reliable
evaluation of luminal morphology, detailed assessment of strut
apposition, and accurate estimation of NT. In addition, the
heterogeneity of appearance of the struts of the Absorb BVS in OCT
permits identification of the correspondence between baseline and
follow-up examinations and use this information for more reliable
reconstruction of the baseline luminal surface (Gutierrez-Chico et
al., Circ J 2012; 76:342-50). The high resolution of OCT allowed
confirmation for the first time in vivo the findings of
computational flow dynamic studies on theoretical models and
demonstrate that the thick protruded struts disrupt flow resulting
in recirculation zones in front and especially behind the struts.
These regions are exposed to low ESS (ESS was <1 Pa in 61% of
surface of the studied segments) which appears to promote vessel
wall healing (Stone, et al., Circulation 2011; 124:763-5).
[0095] In contrast to previous reports which showed that
rapamycin-analogues abrogate the effect of ESS on neointimal
formation, a statistically significant correlation was found
between ESS and NT in all studied segments implanted with an
everolimus eluted BVS (e.g., Papafaklis, JACC Cardiovasc Interv
2010; 3:1181-9). This discrepancy should be attributed to the more
reliable evaluation of NT thickness and baseline ESS patterns in
the segments reconstructed by OCT data as well as to the longer
follow-up period. In previous studies the association between NT
and ESS was evaluated at 6 and 9 months follow-up; only 3 or 6
months after the complete elution of the antiproliferative drug
(Yazdani et al., 2011; 7:835-43). In Absorb BVS 80% of the
everolimus elution is released within the first month after device
implantation. It can be speculated that after the first month the
low ESS promoted neointimal formation resulting in a negative
association between ESS at baseline and neointimal formation at 1
year follow-up (Ormiston et al., Lancet 2008; 371:899-907). The
negative association between ESS and NT may result in treatment
with bioabsorbable stents with different scaffold materials,
coating materials, and drugs.
[0096] The analysis described herein is focused on the association
between ESS and NT at 1 year follow-up and not at other time points
(i.e. at 3 years follow-up or at 6 months or 2 years follow-up
using the data of ABSORB Cohort B1 group) for the following
reasons: 1) half of the baseline OCT examinations in the Cohort B1
group were performed by an M-3 Time Domain system which has
different radial and axial resolution and image quality from the
C7XR Fourier Domain system and thus it is not feasible to find
corresponding struts between baseline and follow-up examinations,
2) our objective was not to compare our findings with the results
of the IVUS based reconstruction studies in metallic drug eluting
stents but to examine the midterm effect of ESS on NT where the
antiproliferative drug has been eluted and the effect of vessel
wall injury has been dissipated and 3) although it would be
interesting to compare the association between ESS and NT at 2
different follow-up time points (i.e. at 1 year follow-up and
3-year follow-up)--as it has been shown that neointimal tissue
continues to develop--the proposed analysis cannot be applied at
2-year or 3-year follow-up since the scaffold loses its structural
integrity after 1 year and expands; thus we cannot approximate the
baseline luminal surface in the scaffolded segment based on the
location of the struts at 2 or 3 years follow-up (e.g., Ormiston et
al., Circ Cardiovasc Interv 2012; 5:620-32).
[0097] This appears to be the first study which examines the effect
of ESS on neointimal proliferation post bioresorbable scaffold
implantation. It was found that the depolymerization of the
scaffold's struts does not impede the mechano-transduction pathways
that regulate the response of the free vessel wall to the local
hemodynamic micro-environment (e.g., Oberhauser et al.,
EuroIntervention 2009; 5 Suppl F:F15-22). Hence, the current
configuration (strut thickness: 156 .mu.m) and composition
(poly-L-lactide struts, covered by a thin layer of an amorphous
matrix of poly-D,L-lactide that controls the release of the
antiproliferative drug--everolimus) of the Absorb BVS provides a
template for the formation of a potentially protective thin layer
of neointimal tissue which without restricting the luminal
dimensions, covers the underlying plaque and the scaffold's struts,
minimizing the risk for late scaffold thrombosis.
[0098] The observations regarding the relationship between ESS and
neointimal proliferation may also apply to other bioabsorbable
stents made from other scaffold materials, coating polymers, and
drugs. Scaffold and coating polymers can include, polylactide-based
(PLA-based) polymers such as poly(D,L-lactide), poly(D,L-lactide)
96/4, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),
poly(D,L-lactide-co-glycolide), poly(L-lactide-co-caprolactone),
poly(D,L-lactide-co-caprolactone), and poly(D, L-lactide) made from
polymerization of a racemic mixture of L- and D-lactides. The
caprolactone copolymers may have 1 to 5 mol % or wt % caprolactone
units. A scaffold or coating polymer may be a blend or copolymer of
PLLA, PLGA, and PCL. The coating polymer may also be a blend of any
combination of the above polymers. The coating polymer may also be
a blend of a PLA based polymer and polycaprolactone with 1 to 5 mol
% or wt % of polycaprolactone. Any combination of the above
polymers can be used for scaffold and coating polymers.
[0099] Scaffold materials may also include bioerodible metals and
metal alloys, for example, magnesium, magnesium alloys, iron, and
iron alloys. The bioerodible metallic scaffold may further include
a drug delivery coating including any of the coating polymers
disclosed.
[0100] The stent or scaffold may also have no drug delivery
coating. The stent or scaffold may have a drug coating of a neat
drug, i.e., with no polymer. The stent or scaffold may also have
drug dispersed within the scaffold with or without a drug-delivery
coating.
[0101] The drug delivery coating of any of the stents disclosed can
include one or more drugs. Exemplary drugs include, but are not
limited to, rapamycin, structural derivatives and functional
analogues of rapamycin, biolimus, everolimus, merilimus, myolimus,
novolimus, paclitaxel, 16-pent-2-ynyloxy-32(S)-dihydro-rapamycin,
ridaforolimus, sirolimus, tacrolimus, temsirolimus, clobetasol, and
zotarolimus. Embodiments may include any combination of drug,
scaffold material, and coating polymer. An exemplary embodiment may
include a scaffold made of a polylactide-based polymer and a
coating including the same or different polylactide-based polymer
and Novolimus.
[0102] The ratio of drug to polymer in a drug delivery coating may
be 1:5 to 5:1, 1:2 to 2:1, or 1:1. The drug dose per mm of stent
length may be 3 to 4 micrograms (mcg), 4 to 5 mcg, 5 to 6 mcg, 6 to
8 mcg, 3 mcg, 4 mcg, 5 mcg, or 6 mcg.
[0103] The strut thickness of the polymer or metallic scaffolds,
with or without a drug delivery coating, can be 80 to 200 microns,
80 to 100 microns, 100 to 120 microns, 120 to 140 microns, 140 to
160 microns, 160 to 180 microns, 180 to 200 microns, 150 to 200
microns, 170 microns, 165 microns, 125 microns, 150 microns, or 160
microns.
[0104] Exemplary bioabsorbable stents are in Table 4.
TABLE-US-00004 TABLE 4 Exemplary bioabsorbable stents Scaffold
Coating Strut thickness Example Polymer Polymer Drug (microns) 1
PLLA PLA-based, Sirolimus 100, 100 to 110, PDLLA, 120, or 120 PLLA
to 130 2 PLLA None None 100, 100 to 110, 120, or 120 to 130 3 PLLA
None None 170 4 Mg alloy None None 155 5 Mg alloy PLA-based,
Paclitaxel 125 PLLA, or PLGA 6 Mg Alloy PLA-based, Sirolimus 150
PLLA, or PLGA 7 PLA- PLA-based Novolimus or 150, 100 to based
Myolimus 140, 140 to 160 8 PLA- PLA-based Sirolimus 150 to 170, 160
based
[0105] The molecular weight in terms of number average or weight
average molecular weight of scaffold polymer may be 70 to 100 kDa,
90 to 100 kDa, 100 to 150 kDA, 150 to 200 kDa, 200 to 250 kDa, 250
to 300 kDa, 300 to 350 kDa, 350 to 400 kDa, 400 to 500 kDa, 500 to
750 kDa, 750 to 1000 kDa, 1000 to 1200 kDa, or greater than 1200
kDa. The intrinsic viscosity of the scaffold polymer in units of
dL/g may be 2 to 2.5, 2.5 to 3, 3 to 3.5, 3.5 to 4 to 4.5, 4.5 to
5, 5 to 5.5, 5.5 to 6, 6 to 6.5, 6.5 to 7, 7 to 7.5, 7.5, 7.5 to 8,
8 to 8.5, and 8.5 to 9.
[0106] Referring to FIG. 1C, the strut cross-section can have a T/W
greater than 1, for example, 1 to 1.2, 1.2 to 1.3, 1.3 to 1.5, 1.5
to 1.8, 1.8 to 2, 2 to 2.5, or greater than 1.2, 1.3, 1.5, 1.8, 2,
or 2.5 2.5. In the case of T/W greater than 1, it is expected that
the blood flow disruption and the ESS at the top of the strut would
increase as T/W increases. Based on the negative or inverse
correlation between ESS and neointimal proliferation, it is further
expected the neointimal proliferation would decrease as the T/W
increases. Alternatively, the strut cross-section can have a T/W
less than 1, for example, 0.9 to 1, 0.7 to 0.9, or 0.5 to 0.7, or
0.5 to 0.7 or less than 0.9, 0.7, 0.5, 0.3, 0.2, or less than 0.2.
It is expected that the blood flow disruption and ESS decreases at
the top of the strut would decrease as T/W decreases. Based on the
negative correlation between ESS and neointimal proliferation, it
is further expected the neointimal proliferation would increase as
the T/W decreases.
[0107] Therefore, the T/W can be adjusted to obtain a desired
protective layer over the top of the strut without restricting the
luminal dimensions and covering underlying plaque and the scaffold
struts to minimize risk of late stent thrombosis.
[0108] The T/W can be adjusted so that at baseline the scaffolded
segments were exposed to a predominantly low ESS environment, at
least 60% of the measured ESS may be less than 2 Pa, less than 1
Pa, or less than 0.5 Pa and at follow-up, the mean neointima
thickness may be between 90 and 120 .mu.m, 100 and 115 .mu.m, or
100 and 110 .mu.m while the percentage scaffold volume obstruction
may be less than 5%, less than 10%, less than 15%, less than 20%,
between 5 and 10%, between 10 and 15%, between 15 and 20%, or
between 10 and 20%.
[0109] Methods of treatment of patients in need of treatment of
coronary heart disease can be based on or modified by any of the
observations herein such as the negative or inverse correlation
between ESS and NT resulting from deployment of a bioabsorbable
scaffold. The steps can apply to any of the bioabsorbable scaffolds
described herein. The methods of treatment can be based on or
modified include one or more steps. The method of treatment can
include identifying a bioabsorbable as providing a negative
correlation between ESS and NT developing at a time within a year
after deployment of the scaffold. The development of the negative
correlation can be identified as present or developing between
deployment and 3 months, between 3 and 6 months after deployment,
between 6 and 9 months after deployment, or between 9 months and 1
year after deployment. The methods of treatment can include
selecting the bioabsorbable scaffold based on the negative
correlation between the ESS and NT. The methods of treatment can
include selecting the bioabsorbable scaffold over another stent or
scaffold based on the negative or inverse correlation between the
ESS and NT.
[0110] Significant limitations of the current analysis are the
assumptions that the reconstructed arteries were straight segments
and that the scaffold was symmetrically expanded. To minimize the
error introduced by the first approximation we included relatively
straight coronary arteries, as of present, there is no method that
has been demonstrated to reliably fuse frequency domain OCT and
angiographic data for complete coronary representation. We have
recently reported a high minimal luminal/maximal luminal diameter
ratio (0.85.+-.0.08) in IVUS cross sectional images of segments
implanted with an Absorb BVS 1.1 fact that indicates a symmetric
expansion of the device (Brugaletta, et al., Catheter Cardiovasc
Interv 2012; 79:19-28). However, potential asymmetries in
scaffold's expansion which may have affected the estimated
association between ESS and NT cannot be excluded. The effect of
malapposed struts on local hemodynanics was not taken into account
in this analysis. Considering the overall low reported prevalence
of malapposed struts and the fact that we excluded segments with
extensive malapposition, it is unlikely for this approximation to
have affected our results (Gomez-Lara et al., JACC Cardiovasc
Interv 2011; 4:992-1001).
[0111] Serial OCT data to reconstruct the coronaries and evaluate
the effect of the hemodynamic micro-environment on neointimal
formation after Absorb BVS implantation. A statistically
significant inverse association was found between ESS and NT in all
the studied segments. These findings underscore the role of local
hemodynamic milieu on vessel wall healing and should be taken into
consideration in the design of bioresorbable devices.
* * * * *